The family of receptors for IgG (FcγR) plays an essential role in antibody-mediated effector functions of the immune system. However, the specific contribution of each of the FcγR classes to in vivo immune reactions is still unclear. Here, we demonstrate that mice deficient for the ligand-binding α chain of FcγRIII lack NK cell–mediated antibody-dependent cytotoxicity and phagocytosis of IgG1-coated particles by macrophages. Strikingly, these mice lack IgG-mediated mast cell degranulation, are resistant to IgG-dependent passive cutaneous anaphylaxis, and exhibit an impaired Arthus reaction. These results indicate a prominent role for FcγRIII in inflammatory and anaphylactic responses, making this receptor a potential target in immunotherapy.